Enantioconvergent Access to the Enantiomerically Pure Building Blocks (+)- or (-)-4-Hydroxy-3-methyl-2-cyclohexenone Using a Chemoenzymatic Process

Abstract

A convenient chemoenzymatic enantioconvergent access to enantiomerically pure (+)- or (-)-4-hydroxy-3-methyl-2-cyclohexenone is described using a one-pot two-step kinetic resolution-stereoinversion protocol followed by hydrolysis. The key step of the sequence is the spontaneous elimination of an undesired stereocenter. The choice between enzymatic acyl transfer or ester alcoholysis of the corresponding racemic starting material, together with the selectivity of a lipase, determines the absolute configuration of the desired single enantiomer.

Key words

enantioconvergence - biocatalysis - kinetic resolution - stereoinversion - chiral building blocks

References and Notes

• 1 Vargas D. Urbatsch LE. Fischer NH. Phytochemistry  1988,  27:  1413 
• 2 Barrero AF. Alvarez-Manzaneda EJ. Herrador MM. Alvarez-Manzaneda R. Quilez J. Chahboun R. Linares P. Rivas A. Tetrahedron Lett.  1999,  40:  8273 
• 3 Bieber LW. Krebs HC. Schaefer W. Phytochemistry  1994,  35:  1027 
• 4 Ksebati MB. Schmitz FJ. Gunasekara SP. J. Org. Chem.  1988,  53:  3917 
• 5a Galano J.-M. Audran G. Monti H. Tetrahedron  2000,  56:  7477 
• 5b Audran G. Galano J.-M. Monti H. Eur. J. Org. Chem.  2001,  2293 
• 5c Uttaro J.-P. Audran G. Galano J.-M. Monti H. Tetrahedron Lett.  2002,  43:  2757 
• 5d Audran G. Uttaro J.-P. Monti H. Synlett  2002,  1261 
• 5e Uttaro J.-P. Audran G. Palombo E. Monti H. J. Org. Chem.  2003,  68:  5407 
• 5f Uttaro J.-P. Audran G. Monti H. J. Org. Chem.  2005,  70:  3484 
• Recent books:
• 6a Enzymatic Reaction in Organic Media   Koskinen AMP. Klibanov AM. Blackie Academic and Professional; Glasgow: 1996. 
• 6b Bornscheuer UT. Kazlauskas RJ. Hydrolases in Organic Synthesis   Wiley-VCH; Weinheim: 1999. 
• 6c Stereoselective Biocatalysis   Patel RN. Marcel Dekker, Inc.; New York: 2000. 
• 6d Enzyme Catalysis in Organic Synthesis: A Comprehensive Handbook   Drauz K. Waldmann H. Wiley-VCH; Weinheim: 2002. 
• 6e Faber K. Biotransformations in Organic Chemistry   5th ed.:  Springer-Verlag; Berlin: 2004. 
• 6f Bommarius AS. Riebel BR. Biocatalysis   Wiley-VCH; Weinheim: 2004. 
• Recent reviews:
• 7a Roberts SM. J. Chem. Soc., Perkin Trans. 1  2001,  1475 
• 7b Zaks A. Curr. Opin. Chem. Biol.  2001,  5:  130 
• 7c Koeller KM. Wong C.-H. Nature (London)  2001,  409:  232 
• 7d Klibanov AM. Nature (London)  2001,  409:  241 
• 7e Thomas SM. DiCosimo R. Nagarajan V. Trends Biotechnol.  2002,  20:  238 
• 7f Hanefeld U. Org. Biomol. Chem.  2003,  1:  2405 
• 7g Garcia-Junceda E. Garcia-Garcia JF. Fernandez-Mayoralas AB. Fernandez-Mayoralas A. Bioorg. Med. Chem.  2004,  12:  1817 
• 7h Ghanem A. Aboul-Enein HY. Tetrahedron: Asymmetry  2004,  15:  3331 
• 7i Faber K. Kroutil W. Curr. Opin. Chem. Biol.  2005,  9:  181 
• 7j Garcia-Urdiales E. Alfonso I. Gotor V. Chem. Rev.  2005,  105:  313 
• 8a Noyori R. Tokunaga M. Kitamura M. Bull. Chem. Soc. Jpn.  1995,  68:  36 
• 8b Stecher H. Faber K. Synthesis  1997,  1 
• 8c Stürmer R. Angew. Chem., Int. Ed. Engl.  1997,  36:  1173 
• 8d El Gihani MT. Williams JMJ. Biocatal. Biotransform.  1999,  3:  11 
• 8e Strauss UT. Felfer U. Faber K. Tetrahedron: Asymmetry  1999,  10:  107 
• 8f Azerad R. Buisson D. Curr. Opin. Biotechnol.  2000,  11:  565 
• 8g Faber K. Chem. Eur. J.  2001,  7:  5004 
• 8h Huerta FF. Minidis ABE. Bäckvall J.-E. Chem. Soc. Rev.  2001,  30:  321 
• 8i Kim MJ. Ahn Y. Park J. Curr. Opin. Biotechnol.  2002,  13:  578 
• 8j Pàmies O. Bäckvall J.-E. Chem. Rev.  2003,  103:  3247 
• 8k Pellissier H. Tetrahedron  2003,  59:  8291 
• 8l Pàmies O. Bäckvall J.-E. Trends Biotechnol.  2004,  22:  130 
• 8m Turner NJ. Curr. Opin. Chem. Biol.  2004,  8:  114 
• 8n Martín-Matute B. Edin M. Bogár K. Bäckvall J.-E. Angew. Chem. Int. Ed.  2004,  43:  6535 
• 9a Mitsuda S. Umemura T. Hirohara H. Appl. Microbiol. Biotechnol.  1988,  29:  310 
• 9b Danda H. Nagatomi T. Maehara A. Umemura T. Tetrahedron  1991,  47:  8701 
• 9c Mayer SF. Steinreiberg A. Orru RVA. Faber K. J. Org. Chem.  2002,  67:  9115 
• 9d Wallner A. Mang H. Glueck SM. Steinreiber A. Mayer SF. Faber K. Tetrahedron: Asymmetry  2003,  14:  2427 
• 9e Ueberbacher BJ. Osprian I. Mayer SF. Faber K. Eur. J. Org. Chem.  2005,  1266 
• 10a Vänttinen E. Kanerva LT. Tetrahedron: Asymmetry  1995,  6:  1779 
• 10b Pedragosa-Moreau S. Morisseau C. Baratti J. Zylber J. Archelas A. Furstoss R. Tetrahedron  1997,  53:  9707 
• 11 Kazlauskas RJ. Weissfloch ANE. Rappoport AT. Cuccia LA. J. Org. Chem.  1991,  56:  2656 
• For discussions of the cesium effect, see:
• 13a Dijkstra G. Kruizinga WH. Kellogg RM. J. Org. Chem.  1987,  52:  4230 
• 13b Ostrowicki A. Koepp E. Vögtle F. Top. Curr. Chem.  1992,  161:  37 
• 13c Salvatore RN. Nagle AS. Schmidt SE. Jung KW. Org. Lett.  1999,  1:  1893 
• 14a Kruizinga WH. Strijtveen B. Kellogg RM. J. Org. Chem.  1981,  46:  4321 
• 14b Arbelo DO. Castro-Rosario L. Prieto JA. Synth. Commun.  2003,  33:  3211 ; and references cited therein
• 16 Using commercially available AD-mix-α or AD-mix-β, the Sharpless AD reaction applied to 3-methyl-3-cyclohexen-one, also afforded directly the target molecule 1 by an in situ elimination of the tertiary hydroxyl group in 2 (64% yield), but in the racemic form, see: Sharpless KB. Amberg W. Bennani YL. Crispino GA. Hartung J. Jeong K.-S. Kwong H.-L. Morikawa K. Wang Z.-M. Xu D. Zhang X.-L. J. Org. Chem.  1992,  57:  2768 

12

Characterization of Compound 2: white solid; mp 62 °C. IR (KBr): ν = 3412, 1728, 1211, 1159 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 3.80 (dd, J = 7.2, 3.6 Hz, 1 H), 3.07 (s, 2 OH), 2.66 and 2.35 (ABX, J = 14.0, 1.5 Hz, 2 H), 2.49 (dddd, J = 14.2, 7.9, 6.2, 1.7 Hz, 1 H), 2.25 (dddd, J = 14.2, 7.2, 6.0, 1.1 Hz, 1 H), 2.05 (dtd, J = 13.6, 7.2, 6.2 Hz, 1 H), 1.93 (dddd, J = 13.6, 7.9, 6.0, 3.6 Hz, 1 H), 1.24 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 209.8 (C), 75.0 (C), 72.8 (CH), 51.3 (CH₂), 36.8 (CH₂), 28.1 (CH₂), 26.1 (CH₃). Anal. Calcd for C₇H₁₂O₃: C, 58.32; H, 8.39. Found: C, 58.21; H, 8.43.
Characterization of Compound 3: white solid; mp 106 °C. IR (KBr): ν = 3391, 1757, 1723, 1148 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 5.00 (dd, J = 8.8, 4.1 Hz, 1 H), 2.54 and 2.40 (ABX, J = 14.6, 1.7 Hz, 2 H), 2.36 (m, 2 H), 2.18-2.05 (partially overlapped m, 1 H), 2.08 (s, 3 H), 1.97 (m, 1 H), 1.20 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 207.7 (C), 170.4 (C), 75.0 (CH), 73.7 (C), 51.7 (CH₂), 37.4 (CH₂), 26.3 (CH₃), 25.3 (CH₂), 20.9 (CH₃). Anal. Calcd for C₉H₁₄O₄: C, 58.05; H, 7.58. Found: C, 57.89; H, 7.60.

15

CAL-B and RML lipases also showed high enantio-selectivity, but with a slightly lower ee.